Recent years have seen a rapid increase in the number of patients with pruritic symptoms as from atopic dermatitis and atopic conjunctivitis. Also increasing is the number of patients with chronic dermatoses such as xerosis due to excessive dryness caused by diminished lipid between horny cells of the skin and lowered water content of the stratum corneum, typically associated with aging. These diseases are accompanied by an intense itch sensation of obscure etiology and are aggravated by the resulting itch-evoked scratching behavior, possibly inducing inflammations in mucous membranes or skin. Therefore, eliminating an itch sensation, particularly doing so while maintaining the normal water content of the stratum corneum, is crucial to the elimination of those symptoms.
Pharmaceutical preparations conventionally used to treat those cases of chronic dermatitis include steroids for external application, antihistamines, antiallergics and humectants. However, the use of steroids is restricted for the strong side effects they may cause, and no completely satisfactory therapeutic efficacy has been obtained from antihistamines, antiallergics, humectants, etc. In addition, diseases that are ameliorated temporarily in symptoms by those drugs will occasionally recur, showing inadequacy in their therapeutic efficacy.
Heretofore, antipruritics have been assessed by administering histamine, serotonin and other pruritogens into the skin of animals and measuring their itch-evoked scratching behavior. However, it was recently reported that the manifestation of an itch due to pruritic symptoms as in atopic dermatitis is not simply the reaction caused by histamine, etc. that are released from mast cells (J. Dermatological Science 25, 20-28, 2001). What is more, on account of unknown etiology for pruritic symptoms from excessive dryness of the skin, no reliable method has been established for assessing the therapeutics available today.
Therefore, it is desired to unravel the mechanism of action in the manifestation of itch for the purpose of preventing and treating pruritic symptoms as in atopic dermatitis, in particular, those from excessive dryness of the skin, and to develop antipruritics that depend on the new mechanism of action.
Prostaglandins have been considered to be a prurigenic component (J. Am. Acad. Dermatol. 47, 28-32, 2002) but it was recently reported that a prostaglandin receptor agonist is useful as an antipruritic agent against the itch from atopic dermatitis (see WO03/070252). However, many of the substances that act on prostaglandin receptors in general often act not only on a specific receptor but also on other receptors. Therefore, if they act not only on the receptor which should develop the intended pharmaceutical efficacy but also on other receptors, there is the risk of an unwanted physiological reaction of manifesting itself as a side effect or reduced action. For example, prostaglandin D2 acts as an agonist not only on the prostaglandin receptors but also on a thromboxane (TP) receptor and it has the possibility of inducing potent vasoconstriction and platelet aggregation which are TP receptor agonistic actions (The Journal of Pharmacology And Experimental Therapeutics (2003), 305, 347-352, Br. J. Pharmacol. (1989), 96, 688-692). In the presence of such side effects, the utility of a particular prostaglandin receptor agonist as an antipruritic agent is limited.
Therefore, the development of an antipruritic agent having less of the unwanted physiological reactions is desired.